PROJECT SUMMARY/ABSTRACT: The overarching goal of this application is to identify the role of the neonatal Fc receptor (FcRn) in echovirus entry and pathogenesis. We recently identified FcRn as a pan-echovirus receptor. We showed that gene editing of FcRn resulted in reduced echovirus infection of cells, and reciprocally, ectopic expression promoted infection in non-permissive cells. We also found that FcRn bound directly to echoviral particles and enhanced virus attachment to cells. Consistent with these findings, recombinant FcRn protein or monoclonal antibodies to FcRn blocked echovirus infection in multiple cell types. Finally, expression of the human homologue of FcRn rendered neonatal mice permissive to E11 infection by the enteral route and showed that expression of the human, but not mouse, homologue of FcRn restored echovirus infection in non-permissive cell types. However, the precise role of FcRn in echovirus entry and a full analysis of the impact of FcRn on echovirus pathogenesis was not explored. The studies proposed in this application will provide important insights into (1) the role of FcRn in echovirus entry and trafficking in the intestinal epithelium, (2) the role of FcRn in the cell-type specific nature of echovirus infections in the liver, and (3) the role of FcRn in echovirus pathogenesis. Our proposal pioneers research into a variety of aspects of the molecular mechanisms of echovirus infections. Importantly, our development of primary human and mouse stem cell-derived models of the intestinal epithelium, in vitro primary cell-based liver models, and novel in vivo models of echovirus pathogenesis are highly innovative technical advances that will allow us to directly assess the mechanistic basis for a number of aspects of echovirus entry and pathogenesis in physiologically-relevant models. Given our extensive expertise in enterovirus research, we are uniquely positioned to perform these studies, which will provide new paradigms for our understanding of echovirus infections.